Many patents have disclosed a series of 2-(2-pyridinylmethylsulfinyl)benzimidazoles as excellent agents for inhibiting the secretion of gastric acid, for example 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (generic name: Omeprazole), 2-[[3-methy-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methylsulfinyl]-1H-benzimidazole (generic name: Lansoprazole), 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl-methyl)sulfinyl]-1H-benzimidazole] (generic name: Pantoprazole), and 2-[[[4-(3-methoxy)propoxy]-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H benzimidazole (generic name: Rabeprazole). One common technical feature for the preparation of these benzimidazole compounds includes that individual precursors 1, 2, 3 or 4 need to undergo similar oxidation reactions to form sulfinyl final products. According to European Patent EP0302720, a method for preparing Lansoprazole comprises oxidizing 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole using H2O2 in the presence of a V2O5 catalyst. Other than the above-mentioned V2O5/H2O2 method, other oxidation methods for preparing Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole include m-chloroperbenzoic acid (MCPBA) (U.S. Pat. Nos. 4,628,098, 5,386,032, 6,043,371, 6,191,148 and US patent publication No. 2004/0209918 A1), sodium perborate tetrahydrate (NaBO3·4H2O)/H2O2 [WO99/02521(1999)], ammonium molybdate ((NH4)2MoO4)/H2O2 (ES Patent 2,036,948 (1993)), sodium hypochloride (NaClO/TEMPO) [U.S. Pat. No. 6,423,846], Ti(IV)-isoproxide/diisopropylethylamine (U.S. Pat. No. 6,303,788).

According to prior art, the inventor of the present invention used V2O5 as an oxidation catalyst and used H2O2 for the oxidation reaction of Lansoprazole and Omeprazole. Although the reaction ratio can reach above 90% and the oxidation by-products can be controlled to be within 1-2%, the reaction products are liable to become black and cannot be discolored. Therefore, the method is rather difficult in quality control. MCPBA is a conventional catalyst commonly used in the oxidation production of Omeprazole, Lansoprazole, Pantoprazole, and Rabeprazole, etc. However, when MCPBA is used as an oxidant, the reaction temperature is −20° C.˜−60° C., and MCPBA is expensive. Under consideration of the low-temperature reaction condition and the production cost, such a method has substantial difficulties in mass production. The inventor of the present invention also conducted investigations in using NaBO3·4H2O/H2O2 for the oxidation reaction of Lansoprazole, wherein, even though the reaction ratio can reach around 90%, excessive amount (5%-10%) of oxidation by-products having the following formula I and II are formed:
The physical properties of the by-products I and II are rather close to the physical properties of the desired product. Thus, the desired product, after crystallization purification of the reaction product mixture, are rather difficult to be separated from the by-products I and II. If further elaborate purifications are performed, the yield is liable to drop dramatically.
When (NH4)2MoO4/H2O2 (ES Patent 2,036,948 (1993)) is used as an oxidant rather than NaBO3·4H2O/H2O2, more oxidation by-products I and II (8˜20%) are produced, and the total yield is about 71-75%. Moreover, the reaction temperature is of 0-5° C. (Examples 16 and 17, ES Patent 2,036,948), which requires additional energy consumption for the low reaction temperature. Thus, such a process is not industrially feasible.
It can be understood from the above that the industry is still looking for a method for commercially mass production of 2-(2-pyridinylmethylsulfinyl)benzimidazoles, such as Omeprazole, Lansoprazole and Pantoprazole, with mild reaction conditions, capable of effectively inhibiting excessive formation of the oxidation by-products I and II, and simple in purification of the desired products.